tbuckley/cabot-search huggingface dataset:
Treatment of Porokeratosis Ptychotropica With a Topical Combination of Cholesterol and Simvastatin
Authors: Marta Albanell-Fernández, Mar Luque-Luna, Carmen López-Cabezas, Francesc Alamon-Reig, Natalia Espinosa-Villaseñor, Lorena Barboza-Guadagnini, José M. Mascaró
Journal: JAMA Dermatology (2023)

This case report describes 2 patients with Ptychotropic porokeratosis who were treated with a combination of cholesterol and simvastatin.
Trends in the Prevalence of Eczema Among US Children by Age, Sex, Race, and Ethnicity From 1997 to 2018
Authors: Siri Choragudi, Gil Yosipovitch
Journal: JAMA Dermatology (2023)

This cross-sectional study of National Health Interview Survey data examines differences among sociodemographic subgroups in reported incidence of eczema in children in the US.
Osthole regulates N6‐methyladenosine‐modified TGM2 to inhibit the progression of rheumatoid arthritis and associated interstitial lung disease
Authors: Xian Lin, Jian Chen, Cheng Tao, Lianxiang Luo, Juan He, Qingwen Wang
Journal: MedComm (2023)

Abstract Rheumatoid arthritis (RA) is an inflammatory autoimmune disease, and RA interstitial lung disease (ILD) is a severe complication of RA. This investigation aims to determine the effect and underlying mechanism of osthole (OS), which could be extracted from Cnidium , Angelica , and Citrus plants and evaluate the role of transglutaminase 2 (TGM2) in RA and RA‐ILD. In this work, OS downregulated TGM2 to exert its additive effect with methotrexate and suppress the proliferation, migration, and invasion of RA‐fibroblast‐like synoviocytes (FLS) by attenuating NF‐κB signaling, resulting in the suppression of RA progression. Interestingly, WTAP‐mediated N6‐methyladenosine modification of TGM2 and Myc‐mediated WTAP transcription cooperatively contributed to the formation of a TGM2/Myc/WTAP‐positive feedback loop through upregulating NF‐κB signaling. Moreover, OS could downregulate the activation of the TGM2/Myc/WTAP‐positive feedback circuit. Furthermore, OS restrained the proliferation and polarization of M2 macrophages to inhibit the aggregation of lung interstitial CD11b + macrophages, and the effectiveness and non‐toxicity of OS in suppressing RA and RA‐ILD progression were verified in vivo. Finally, bioinformatics analyses validated the importance and the clinical significance of the OS‐regulated molecular network. Taken together, our work emphasized OS as an effective drug candidate and TGM2 as a promising target for RA and RA‐ILD treatment.
Autoimmune Lymphoproliferative Syndrome (ALPS) Disease and ALPS Phenotype: Are They Two Distinct Entities?
Authors: Elena Palmisani, Maurizio Miano, Alice Grossi, Marina Lanciotti, Michela Lupia, Paola Terranova, Isabella Ceccherini, Eugenia Montanari, Michaela Calvillo, Filomena Pierri, Concetta Micalizzi, Rosario Maggiore, Daniela Guardo, Sabrina Zanardi, Elena Facchini, Angela Maggio, Elena Mastrodicasa, Paola Corti, Giovanna Russo, Marta Pillon, Piero Farruggia, Simone Cesaro, Angelica Barone, Francesca Tosetti, Ugo Ramenghi, Nicoletta Crescenzio, Jack Bleesing, Carlo Dufour, Francesca Fioredda
Journal: HemaSphere (2023)

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of lymphocyte homeostasis classically due to mutation of FAS, FASL, and CASP10 genes (ALPS-FAS/CASP10). Despite recent progress, about one-third of ALPS patients does not carry classical mutations and still remains gene orphan (ALPS-U, undetermined genetic defects). The aims of the present study were to compare the clinical and immunological features of ALPS-FAS/CASP10 versus those of ALPS-U affected subjects and to deepen the genetic characteristics of this latter group. Demographical, anamnestic, biochemical data were retrieved from medical record of 46 ALPS subjects. An enlarged panel of genes (next-generation sequencing) was applied to the ALPS-U group. ALPS-U subjects showed a more complex phenotype if compared to ALPS-FAS/CASP10 group, characterized by multiorgan involvement ( P = 0.001) and positivity of autoimmune markers ( P = 0.02). Multilineage cytopenia was present in both groups without differences with the exception of lymphocytopenia and autoimmune neutropenia that were more frequent in ALPS-U than in the ALPS-FAS/CASP10 group ( P = 0.01 and P = 0.04). First- and second-line treatments were able to control the symptoms in 100% of the ALPS-FAS/CASP10 patients, while 63% of ALPS-U needed &gt;2 lines of treatment and remission in some cases was obtained only after target therapy. In the ALPS-U group, we found in 14 of 28 (50%) patients 19 variants; of these, 4 of 19 (21%) were known as pathogenic and 8 of 19 (42%) as likely pathogenic. A characteristic flow cytometry panel including CD3CD4-CD8-+TCRαβ+, CD3+CD25+/CD3HLADR+, TCR αβ+ B220+, and CD19+CD27+ identified the ALPS-FAS/CASP10 group. ALPS-U seems to represent a distinct entity from ALPS-FAS/CASP10; this is relevant for management and tailored treatments whenever available.
COVID-19 Vaccination During Pregnancy Protected Infants
Authors: Emily Harris
Journal: JAMA (2023)

Study: No New SARS-CoV-2 Variants in Recent Outbreak in China After relaxing its "zero-COVID policy" in early December 2022, China's SARS-CoV-2 infections surged, stoking concerns that new variants might appear.But none emerged in a genomic analysis of 413 COVID-19 cases collected in Beijing between November 14 and December 20, 2022.Two Omicron subvariants-BA.5.2 and BF.7-represented more than 90% of local infections, researchers in China reported in The Lancet.The authors of a corresponding editorial noted that because the study only covered cases from a few weeks after China's policy change, it would not have detected variants that might have emerged later.They also emphasized that the study cases were in Beijing and might not reflect conditions in other regions of China.
Addressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T cell–Secreted Cytokines
Authors: Yoshinaga Ito, Deng Pan, Wubing Zhang, Xixi Zhang, Tiffany Y. Juan, Jason W. Pyrdol, Oleksandr Kyrysyuk, John G. Doench, X. Shirley Liu, Kai W. Wucherpfennig
Journal: Cancer Discovery (2023)

Tumor heterogeneity is a major barrier to cancer therapy, including immunotherapy. Activated T cells can efficiently kill tumor cells following recognition of MHC class I (MHC-I)-bound peptides, but this selection pressure favors outgrowth of MHC-I-deficient tumor cells. We performed a genome-scale screen to discover alternative pathways for T cell-mediated killing of MHC-I-deficient tumor cells. Autophagy and TNF signaling emerged as top pathways, and inactivation of Rnf31 (TNF signaling) and Atg5 (autophagy) sensitized MHC-I-deficient tumor cells to apoptosis by T cell-derived cytokines. Mechanistic studies demonstrated that inhibition of autophagy amplified proapoptotic effects of cytokines in tumor cells. Antigens from apoptotic MHC-I-deficient tumor cells were efficiently cross-presented by dendritic cells, resulting in heightened tumor infiltration by IFNγ-and TNFα-producing T cells. Tumors with a substantial population of MHC-I-deficient cancer cells could be controlled by T cells when both pathways were targeted using genetic or pharmacologic approaches. Tumor heterogeneity is a major barrier to immunotherapy. We show that MHC-I-deficient tumor cells are forced into apoptosis by T cell-derived cytokines when TNF signaling and autophagy pathways are targeted. This approach enables T cell-mediated elimination of tumors with a substantial population of resistant, MHC-I-deficient tumor cells. This article is highlighted in the In This Issue feature, p. 1027.
Induction of immunosuppressive <scp>CD39</scp> but not the trafficking <scp>C‐C</scp> chemokine receptor 4 on Treg during <scp>LAR</scp> in mite allergic asthma
Authors: Virginie Doyen, Anh Poirot, Myriam Maumy‐Bertrand, Frederic Bertrand, Naji Khayath, Nathalie Domis, Frederic de Blay
Journal: Allergy (2023)

Table S1: Figure S1: Figure S2: Figure S3: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
To improve mental healthcare we first need to build respect for psychiatry
Authors: Adele Waters
Journal: BMJ (2023)

Lade Smith discovered she wanted to be a doctor in Manchester Central Library, then a psychiatry placement was “a lightbulb moment”— now she is set to become the first black woman to lead a UK medical royal college. She’s determined to use the Royal College of Psychiatrists’ influence to improve things for patients and professionals, writes <b>Adele Waters</b>
Exposure to Air Pollution and Emergency Department Visits During the First Year of Life Among Preterm and Full-term Infants
Authors: Anaïs Teyton, Rebecca J. Baer, Tarik Benmarhnia, Gretchen Bandoli
Journal: JAMA Network Open (2023)

Importance Previous studies have focused on exposure to fine particulate matter 2.5 μm or less in diameter (PM 2.5 ) and on birth outcome risks; however, few studies have evaluated the health consequences of PM 2.5 exposure on infants during their first year of life and whether prematurity could exacerbate such risks. Objective To assess the association of PM 2.5 exposure with emergency department (ED) visits during the first year of life and determine whether preterm birth status modifies the association. Design, Setting, and Participants This individual-level cohort study used data from the Study of Outcomes in Mothers and Infants cohort, which includes all live-born, singleton deliveries in California. Data from infants’ health records through their first birthday were included. Participants included 2 175 180 infants born between 2014 and 2018, and complete data were included for an analytic sample of 1 983 700 (91.2%). Analysis was conducted from October 2021 to September 2022. Exposures Weekly PM 2.5 exposure at the residential ZIP code at birth was estimated from an ensemble model combining multiple machine learning algorithms and several potentially associated variables. Main Outcomes and Measures Main outcomes included the first all-cause ED visit and the first infection- and respiratory-related visits separately. Hypotheses were generated after data collection and prior to analysis. Pooled logistic regression models with a discrete time approach assessed PM 2.5 exposure and time to ED visits during each week of the first year of life and across the entire year. Preterm birth status, sex, and payment type for delivery were assessed as effect modifiers. Results Of the 1 983 700 infants, 979 038 (49.4%) were female, 966 349 (48.7%) were Hispanic, and 142 081 (7.2%) were preterm. Across the first year of life, the odds of an ED visit for any cause were greater among both preterm (AOR, 1.056; 95% CI, 1.048-1.064) and full-term (AOR, 1.051; 95% CI, 1.049-1.053) infants for each 5-μg/m 3 increase in exposure to PM 2.5 . Elevated odds were also observed for infection-related ED visit (preterm: AOR, 1.035; 95% CI, 1.001-1.069; full-term: AOR, 1.053; 95% CI, 1.044-1.062) and first respiratory-related ED visit (preterm: AOR, 1.080; 95% CI, 1.067-1.093; full-term: AOR,1.065; 95% CI, 1.061-1.069). For both preterm and full-term infants, ages 18 to 23 weeks were associated with the greatest odds of all-cause ED visits (AORs ranged from 1.034; 95% CI, 0.976-1.094 to 1.077; 95% CI, 1.022-1.135). Conclusions and Relevance Increasing PM 2.5 exposure was associated with an increased ED visit risk for both preterm and full-term infants during the first year of life, which may have implications for interventions aimed at minimizing air pollution.
B-1 plasma cells require non-cognate CD4 T cell help to generate a unique repertoire of natural IgM
Authors: Fauna L. Smith, Hannah P. Savage, Zheng Luo, Christopher M. Tipton, F. Eun-Hyung Lee, April C. Apostol, Anna E. Beaudin, Diego A. Lopez, Ingvill Jensen, Stefan Keller, Nicole Baumgarth
Journal: The Journal of Experimental Medicine (2023)

Evolutionarily conserved, “natural” (n)IgM is broadly reactive to both self and foreign antigens. Its selective deficiency leads to increases in autoimmune diseases and infections. In mice, nIgM is secreted independent of microbial exposure to bone marrow (BM) and spleen B-1 cell–derived plasma cells (B-1PC), generating the majority of nIgM, or by B-1 cells that remain non-terminally differentiated (B-1sec). Thus, it has been assumed that the nIgM repertoire is broadly reflective of the repertoire of body cavity B-1 cells. Studies here reveal, however, that B-1PC generate a distinct, oligoclonal nIgM repertoire, characterized by short CDR3 variable immunoglobulin heavy chain regions, 7–8 amino acids in length, some public, many arising from convergent rearrangements, while specificities previously associated with nIgM were generated by a population of IgM-secreting B-1 (B-1sec). BM, but not spleen B-1PC, or B-1sec also required the presence of TCRαβ CD4 T cells for their development from fetal precursors. Together, the studies identify important previously unknown characteristics of the nIgM pool.
A prospective phase II trial of neoadjuvant sintilimab in muscle-invasive urothelial carcinoma of bladder.
Authors: Fangning Wan, Chengyuan Gu, Chunguang Ma, Yiping Zhu, Yijun Shen, Dingwei Ye
Journal: Journal of Clinical Oncology (2023)

509 Background: To assess the efficacy and safety of the PD-1 antibody in neoadjuvant setting of muscle-invasive urothelial carcinoma of bladder (MIBC). Methods: In this prospective phase II trial (ChiCTR2000032730), eligible patients were cT2-T4 N0 MIBC, and were considered eligible for radical cystectomy (RC). Patients received sintilimab 200 mg on days 1, study treatment was repeated every 21 days up to 3 cycles before surgery. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included incidence of surgical related delayed events, relapse free survival, overall survival and safety. Results: Between Aug 2020 and Sep 2022, 15 patients (median age: 69, male 93.3%, PS=1 100%) were enrolled. The majority of patients (93.3%) completed the planned (median, 3; range 2 to 4) cycles of sintilimab without significant toxicities. The most common adverse events included hematuria (3/15), proteinuria (2/15), hypophosphatemia (2/15), hypoalbuminemia (2/15) and dysuria (2/15). Among the 15 patients who completed study treatment, 9 patients (60.0%) received RC. Among 6 patients who did not revive RC, 1 due to myasthenia gravis related to sintilimab, 1 due to progression disease, 3 patients refused RC due to bladder preserving, and 1 due to cardiac comorbidity unrelated to sintilimab. Pathologic results revealed 6 pCR (ypT0, 66.7%), 1 ypT0N1, 1 ypT2N0 and 1ypT4N0. At a median follow up of 181 days, they all had no disease recurrence and median DFS was not reached. 2 patients died of disease progression (1 refused RC, 1 had PD before RC). Conclusions: Neoadjuvant sintilimab was feasible and provided meaningful pathologic responses in patients with MIBC. Clinical trial information: ChiCTR2000032730 .
Predictor of adverse pathology in patients who underwent deferred radical prostatectomy following active surveillance: Results from multi-institutional prospective observational cohort in the PRIAS-JAPAN.
Authors: Yoichiro Tohi, Ryou Ishikawa, Takuma Kato, Jimpei Miyakawa, Ryuji Matsumoto, Keiichiro Mori, Koji Mitsuzuka, Junichi Inokuchi, Masafumi Matsumura, Kenichiro Shiga, Hirohito Naito, Yasuo Kohjimoto, Norihiko Kawamura, Masaharu Inoue, Shusuke Akamatsu, Naoki Terada, Yoshiyuki Miyazawa, Shintaro Narita, Reiji Haba, Mikio Sugimoto
Journal: Journal of Clinical Oncology (2023)

350 Background: Intraductal carcinoma of the prostate (IDC-P) and invasive cribriform are key prognostic pathologies among early stage prostate cancer patients; however, predictors of adverse pathology, including these types, remain unknown. In men who opted for active surveillance (AS), we aimed to examine the association between adverse pathology and patient characteristics, utilizing radical prostatectomy (RP) specimens. Methods: We re-reviewed available RP specimens from 1035 men prospectively enrolled in the PRIAS-JAPAN cohort between January 2010 and September 2020. We defined adverse pathology on RP specimen as Gleason grade group of ≥3, pT-stage≥T3, pN positivity, or the presence of IDC-P or invasive cribriform. And, we examined the predictive factors associated with adverse pathology, using factors at AS enrollment and before RP. Results: Out of 162 men underwent RP, available 137 RP specimens were analyzed. The percentage of adverse pathology was 48.9% (67 patients), including 8.8% in IDC-P and 29.9 % in invasive cribriform. Men with adverse pathology had lower prostate specific antigen recurrence-free survival than those without them (log rank P = 0.0189). On multivariate logistic regression analyses, increasing age at AS enrollment and before RP were the predictive factors for adverse pathology (Odds ratio [OR], 1.1; 95% confidence interval [CI]: 1.02-1.19, P = 0.0178, OR, 1.12; 95% CI: 1.02-1.22, P=0.0126), not magnetic resonance imaging findings. Conclusions: Aging is significantly associated with adverse pathology including IDC-P or cribriform. The results suggest that relaxing scheduled examinations during AS depending on age is not practical. Clinical trial information: UMIN000048095 .
Preliminary results from a phase II study of tislelizumab combined with radiotherapy as bladder-preserving treatment for patients with high-risk non-muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette-Guerin (BCG).
Authors: Zhiyong Li, Liru He, Xiangdong Li, Kai Yao, Yang Liu, Zike Qin, Yunlin Ye, Fangjian Zhou, Zhuowei Liu
Journal: Journal of Clinical Oncology (2023)

510 Background: Radical cystectomy (RC) was recommended to patients (pts) with HR NMIBC BCG-unresponsive papillary tumors. Clinical unmet need was to explore non-surgical treatment options for pts who were ineligible for or refused RC. Our study aimed to evaluate the efficacy and safety of tislelizumab combined with radiotherapy as bladder-preserving treatment for pts with HR NMIBC unresponsive to BCG. Methods: This open-label, single arm phase II study enrolled pts with HR NMIBC BCG-unresponsive papillary tumors (high-grade Ta or T1 tumors without carcinoma in situ). The papillary tumors should be removed all visible lesions by transurethral resection of bladder tumor (TURBT). Within 2 weeks after TURBT, eligible pts received tislelizumab 200 mg in day 1 (D1), every 21 days for eight cycles and a total radiotherapy dose of 60-66 GY in 30-33 fractions over seven weeks. The primary end point was disease-free survival (DFS) rate at 12 months (defined as no reappearance of high grade or T1 tumors or clinical stage development after the therapy). Secondary end points were bladder-preservation rate, OS and safety. Our study anticipated a DFS rate at 12 months was 45% and the study would enroll 32 pts to meet the primary endpoint. Results: By Sep. 2022, 14 eligible pts were enrolled. Ten pts have completed therapy and were analyzed (male 90.0%; median age 58 years (31-79); pure TCC 100%; median tumor size 1.0 cm (0.5-2.0); 40% multiple papillary tumours; median eGFR, 91.1 mL/(min•1.73m 2 ) (46.1-115.5); high-grade Ta 40.0%, T1 60.0%; median of 11 previous BCG instillations (9-19)). Median follow-up was 20.3 months (9.9-28.1), the median number of tislelizumab cycles was 8 (2-8) and radiotherapy doses was 60 GY (60-66) in 30 fractions. The DFS rate at 12 month was 80.0% (95%CI, 67.4%-92.6%), at 24 month was 60.0% (95%CI, 40.3%-79.7%). Two pts showed reappearance of high-grade Ta and received TURBT, one patient showed stage development from T1N0M0 to M1 disease and received systemic treatment. The bladder-preservation rate at 24 months was 100% (95%CI, 100%-100%). The OS rate at 24 months was 100% (95%CI, 100%-100%). Treatment related adverse events (TRAEs) of any grade were rash (40.0%), neutropenia (10.0%), hyperthyroidism (10.0%), AST/ALT increased (10.0%) and hyperglycaemia (10.0%). 5 pts experienced immune related AEs, including rash (n=4, G1-2), hyperthyroidism (n=1, G2), hyperglycaemia (n=1, G3) and AST/ALT increased (n=1, G3). Conclusions: Our preliminary results supported the use of tislelizumab combined with radiotherapy as a promising bladder-preserving therapy for pts with BCG-unresponsive HR NMIBC who were ineligible for or refused RC. Clinical trial information: ChiCTR2000035275 .
A phase 2, open-label study of neoadjuvant chemotherapy plus tislelizumab followed by radiotherapy-based, bladder-preserving treatment for high risk/locally advanced muscle invasive urothelial bladder cancer (HOPE-02).
Authors: Feng Wen, Tianhai Lin, Peng Zhang, Ping Tan, Xiaonan Zheng, Yali Shen
Journal: Journal of Clinical Oncology (2023)

516 Background: Tri-modality therapy (TMT) is an alternative to radical cystectomy for selected muscle-invasive bladder cancer (MIBC) patients with bladder-preserving will. Neoadjuvant treatment makes chance for imperfect patients to turn into ideal bladder-sparing patients. This phase 2 study aimed to explore the efficacy of neoadjuvant chemotherapy plus tislelizumab followed by radiotherapy as a strategy of bladder-sparing therapy for high risk/locally advanced MIBC (Trial registration number: ChiCTR2100045213). Methods: Pathological and imaging diagnosed cT2-4bN0-3M0-1a MIBC received 3-4 cycles of neoadjuvant chemotherapy (gemcitabine and cisplatin or carboplatin) plus tislelizumab (200mg every three weeks for one year). Radiotherapy (60.4-64.4 Gy /1.8Gy/33-35f to bladder with 50.4 Gy/1.8Gy/28f to pelvic) were given to patients with non- progressed disease (PD) after neoadjuvant therapy. The primary endpoint was complete response rate (CR, including T0/Ta/Tis), and the secondary endpoints were progression-free survival (PFS), bladder-intact disease free survival (BI-DFS), overall survival (OS) and toxicity. Results: The simple size is 43 participants. Until now, 28 patients were included, of which 23 patients received radiotherapy and 16 patients finished efficacy evaluation with imaging and cystoscopic biopsy after radiotherapy. Median follow-up time was 14.2 (1.5-17.4) months (m). Two of the 16 patients were Tis and 14 were T0 after radiotherapy, indicating the primary CR rate were 100%. For the 2 patients with Tis received BCG vaccine intravesical perfusion, and T0 was achieved when the second therapy evaluation. No patient died and only one patient had distant metastasis. The one-year PFS rate, one-year BI-DFS and one-year OS were 100%. Grade 3 and 4 hematological system adverse events were 23.3% and 2.3%. One patient had reduced bladder capacity (100-200 mL) with 2-h intervals of micturition, and 3 patients had frequency with urgency, nocturia and dysuria. Three patients had grade1 immunotherapy related abnormality of thyroidal function and 3 patients suffered from grade 2 myositis. The current bladder-preserving therapies research were well-tolerated with acceptable and manageable toxicities. Conclusions: Neoadjuvant chemotherapy plus tislelizumab followed by radiotherapy showed perfect efficacy and acceptable toxicities, which maybe an optimal strategy for high risk/locally advanced MIBC patients with bladder-preserving willingness. Clinical trial information: ChiCTR2100045213 .